This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of the proposed studies is to investigate the role of Hepatocyte Nuclear Factor-4alpha (HNF-4alpha, NR2A1) in regulation of hepatocyte proliferation. Whereas the role of HNF4alpha in regulation of hepatic differentiation is well characterized, its role in regulation of hepatocyte proliferation is not clear. The central hypothesis is that, HNF4alpha inhibits hepatocyte proliferation via cell cycle inhibitor p21/WAF1 and the HNF4alpha-mediated inhibition of hepatocyte proliferation is critical for liver homeostasis during development and regeneration. The role of HNF4alpha in inhibition of hepatocyte proliferation will be determined using novel mouse models generated using tissue specific gene targeting combined with inducible Cre methodology. We will utilize well-characterized models of hepatocyte proliferation including partial hepatectomy and hepatocellular carcinoma. Further, we will investigate role of cell cycle inhibitor p21/WAF1 in HNF-4alpha-mediated inhibition of hepatocyte proliferation suing cutting-edge techniques such as ChIP assays and double knockout mouse models. The results of this study will not only shed light on crucial cell cycle and organ size regulation mechanisms in the liver, but will also open novel targets for intervention during uncontrolled liver growth as observed in liver cancers.